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Published Online: 30 August 2023

Genetic Contribution to the Heterogeneity of Major Depressive Disorder: Evidence From a Sibling-Based Design Using Swedish National Registers

Thuy-Dung Nguyen, M.Sc., Kaarina Kowalec, Ph.D., Joëlle Pasman, Ph.D., Henrik Larsson, Ph.D., Paul Lichtenstein, Ph.D., Christina Dalman, M.D., Patrick F. Sullivan, M.D., F.R.A.N.Z.C.P., Ralf Kuja-Halkola, Ph.D., and Yi Lu, Ph.D. [email protected]Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 180, Number 10
https://doi.org/10.1176/appi.ajp.20220906
CME
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Abstract

Objective:

Major depressive disorder (MDD) is highly heterogeneous. Standard typology partly captures the disorder’s symptomatic heterogeneity, although whether it adequately captures etiological heterogeneity remains elusive. The aim of this study was to investigate the genetic characterization of MDD heterogeneity.

Methods:

Using Swedish patient register data on 1.5 million individuals, the authors identified 46,255 individuals with specialist-diagnosed MDD. Eighteen subgroups were identified based on nine comparison groups defined by clinical and psychosocial features, including severity, recurrence, comorbidities, suicidality, impairment, disability, care unit, and age at diagnosis. A sibling-based design and classic quantitative genetic models were applied to estimate heritability of MDD subgroups and genetic correlations between subgroups.

Results:

Estimates of heritability ranged from 30.5% to 58.3% across subgroups. The disabled and youth-onset subgroups showed significantly higher heritability (55.1%–58.3%) than the overall MDD sample (45.3%, 95% CI=43.0–47.5), and the subgroups with single-episode MDD and without psychiatric comorbidity showed significantly lower estimates (30.5%–34.4%). Estimates of genetic correlations between the subgroups within comparison groups ranged from 0.33 to 0.90. Seven of nine genetic correlations were significantly smaller than 1, suggesting differences in underlying genetic architecture. These results were largely consistent with previous work using genomic data.

Conclusions:

The findings of differential heritability and partially distinct genetic components in subgroups provide important insights into the genetic heterogeneity of MDD and a deeper etiological understanding of MDD clinical subgroups.

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Supplementary Material

File (appi.ajp.20220906.ds001.pdf)

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 180 • Number 10 • October 1, 2023
Pages: 714 - 722
PubMed: 37644812

History

Received: 2 November 2022
Revision received: 28 April 2023
Accepted: 26 May 2023
Published online: 30 August 2023
Published in print: October 1, 2023

Keywords

  1. Depressive Disorders
  2. Major Depressive Disorder
  3. Genetics / Genomics
  4. Epidemiology
  5. Heterogeneity

Authors

Affiliations

Thuy-Dung Nguyen, M.Sc.
Department of Medical Epidemiology and Biostatistics (Nguyen, Kowalec, Pasman, Larsson, Lichtenstein, Sullivan, Kuja-Halkola, Lu) and Department of Global Public Health (Nguyen, Dalman, Lu), Karolinska Institutet, Stockholm; College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan).
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Kaarina Kowalec, Ph.D.
Department of Medical Epidemiology and Biostatistics (Nguyen, Kowalec, Pasman, Larsson, Lichtenstein, Sullivan, Kuja-Halkola, Lu) and Department of Global Public Health (Nguyen, Dalman, Lu), Karolinska Institutet, Stockholm; College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan).
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Joëlle Pasman, Ph.D.
Department of Medical Epidemiology and Biostatistics (Nguyen, Kowalec, Pasman, Larsson, Lichtenstein, Sullivan, Kuja-Halkola, Lu) and Department of Global Public Health (Nguyen, Dalman, Lu), Karolinska Institutet, Stockholm; College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan).
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Henrik Larsson, Ph.D.
Department of Medical Epidemiology and Biostatistics (Nguyen, Kowalec, Pasman, Larsson, Lichtenstein, Sullivan, Kuja-Halkola, Lu) and Department of Global Public Health (Nguyen, Dalman, Lu), Karolinska Institutet, Stockholm; College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan).
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Paul Lichtenstein, Ph.D.
Department of Medical Epidemiology and Biostatistics (Nguyen, Kowalec, Pasman, Larsson, Lichtenstein, Sullivan, Kuja-Halkola, Lu) and Department of Global Public Health (Nguyen, Dalman, Lu), Karolinska Institutet, Stockholm; College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan).
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Christina Dalman, M.D.
Department of Medical Epidemiology and Biostatistics (Nguyen, Kowalec, Pasman, Larsson, Lichtenstein, Sullivan, Kuja-Halkola, Lu) and Department of Global Public Health (Nguyen, Dalman, Lu), Karolinska Institutet, Stockholm; College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan).
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Patrick F. Sullivan, M.D., F.R.A.N.Z.C.P.
Department of Medical Epidemiology and Biostatistics (Nguyen, Kowalec, Pasman, Larsson, Lichtenstein, Sullivan, Kuja-Halkola, Lu) and Department of Global Public Health (Nguyen, Dalman, Lu), Karolinska Institutet, Stockholm; College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan).
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Ralf Kuja-Halkola, Ph.D.
Department of Medical Epidemiology and Biostatistics (Nguyen, Kowalec, Pasman, Larsson, Lichtenstein, Sullivan, Kuja-Halkola, Lu) and Department of Global Public Health (Nguyen, Dalman, Lu), Karolinska Institutet, Stockholm; College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan).
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Yi Lu, Ph.D. [email protected]
Department of Medical Epidemiology and Biostatistics (Nguyen, Kowalec, Pasman, Larsson, Lichtenstein, Sullivan, Kuja-Halkola, Lu) and Department of Global Public Health (Nguyen, Dalman, Lu), Karolinska Institutet, Stockholm; College of Pharmacy, University of Manitoba, Winnipeg, Canada (Kowalec); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill (Sullivan).
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Notes

Send correspondence to Dr. Lu ([email protected]).
Presented as a poster at the 2021 Virtual World Congress of Psychiatric Genetics, October 11–15, 2021.

Author Contributions

Dr. Kuja-Halkola and Dr. Lu contributed equally.

Funding Information

Supported by NIMH (grant R01 MH123724), the European Union’s Horizon 2020 Research and Innovation Program (grant agreement numbers 847776 and 964874), and the European Research Council (grant agreement ID 101042183).Dr. Larsson has received grants from Shire Pharmaceuticals, personal and speaking fees from Evolan Pharma AB, Medice, and Shire/Takeda Pharmaceuticals, and sponsorship for a conference from Evolan Pharma AB and Shire/Takeda Pharmaceuticals, and he serves as editor-in-chief of JCPP Advances. Dr. Sullivan has served as an advisory committee member for Neumora Therapeutics and is a shareholder. The other authors report no financial relationships with commercial interests.

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